Naturally occurring tolerance acquisition to foods in previously allergic children is characterized by antigen specificity and associated with increased subsets of regulatory T cells

• Published in: Clinical and experimental allergy Vol. 45; no. 11; pp. 1663 - 1672
• Main Authors: Qamar, N., Fishbein, A. B., Erickson, K. A., Cai, M., Szychlinski, C., Bryce, P. J., Schleimer, R. P., Fuleihan, R. L., Singh, A. M.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-11-2015; Wiley Subscription Services, Inc
• Subjects: Adolescent; Allergens - immunology; antigen specificity; Antigens, Surface - metabolism; Arachis - immunology; Arachis hypogaea; Case-Control Studies; CD4 Lymphocyte Count; Child; Child, Preschool; Female; Food - adverse effects; food allergy; Food Hypersensitivity - immunology; Humans; IL-10; Immune Tolerance; Immunoglobulin E - immunology; Immunophenotyping; Infant; Interleukin-10 - biosynthesis; Male; natural tolerance; Phenotype; T regulatory cells; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; antigen specificity; T regulatory cells; food allergy; IL-10; natural tolerance
• ISSN: 0954-7894; 1365-2222
• DOI: 10.1111/cea.12570

Summary
Background
Food allergy affects approximately 6–8% of children, and increasing in prevalence. Some children naturally outgrow their food allergy without intervention, but the mechanisms by which this occurs remain poorly understood. We sought to investigate the role of regulatory T cells in the development of naturally acquired tolerance.
Methods
Fifty‐eight children (1–18 years) with either egg or peanut allergy, recent acquisition of natural tolerance to egg or peanut, or no food allergy were studied. Peripheral blood mononuclear cells (PBMC) from these groups were stimulated with relevant antigen for 48 h and flow cytometry performed to characterize both surface (CD3, CD4, CD25, CD14, CD19, and CD127) and intracellular markers (IL‐10, Foxp3, and IL‐5).
Results
Resting PBMC from naturally tolerant patients had significantly increased CD3+CD4+CD25+CD127loFoxp3+ cells, when compared to allergic or control patients (mean 6.36 vs. 2.37 vs. 2.62%, respectively, P < 0.05). Upon stimulation with relevant antigen, naturally tolerant patients also had increased IL‐10‐expressing CD25+CD127lo cells (6.33 vs. 1.65 vs. 0.7, P < 0.01), Foxp3+ cells (mean 12.6 vs. 5.42 vs. 3%, P < 0.01), and CD4+ cells (mean 4.48 vs. 1.59 vs. 0.87%, P < 0.01); the increase was not observed in PBMCs from allergic or control patients. Additionally, this upregulation was only seen with relevant antigen stimulation and not upon stimulation with unrelated antigen.
Conclusion
The increased CD3+CD4+CD25+CD127lo cells at baseline and upon stimulation and increased induction of IL‐10‐producing cells of several types, including Tr1 cells, from naturally tolerant patients suggests an important role for regulatory T cell subsets in the acquisition of natural tolerance.